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Takeda Sees Cell Gene Therapy In Its Future. Is It Too Late?

Thanks to a $62 billion acquisition of Shire, Takeda is one of the world’s largest developers of rare disease drugs.

Despite that, the 238-year-old Japanese pharmaceutical company lacks any mid- or late-stage cell or gene therapies, two technologies that figure to play a large role in how many rare cancers and inherited diseases will eventually be treated.

It’s a mismatch Takeda is putting substantial effort into addressing. Last week, executives made cell and gene therapy a notable focus of the company’s first R&D day since closing its Shire deal.

“We have a world-class gene therapy platform,” Dan Curran, head of Takeda’s rare disease therapeutic area unit, told investors and Wall Street analysts gathered in New York city.

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“We intend to build on that over the next five years. Because as we look to lead in the second half of [next] decade, we believe patients will demand and we can deliver transformative and curative therapies to patients globally.”

But right now that’s just an ambition. While Takeda has begun to explore how it can improve on current gene therapies, its candidates are early stage and lag their would-be competitors.

“Our heme A program — we’re behind. Our heme B program — we’re behind,” admitted Curran in an interview. “But we’re behind the first generation and when has there only been one generation of anything?”

Takeda’s hemophilia A program is currently in Phase 1, with the hemophilia B candidate about to join it in human testing — well back from leaders BioMarin Pharmaceutical, Spark Therapeutics and Sangamo Therapeutics in hemophilia A and UniQure in hemophilia B.

Curran laid out three priorities for Takeda’s push: exploring whether gene therapy, typically pitched as a one-time treatment, can be re-dosed; lowering the doses currently used for first-generation therapies; and developing alternative gene delivery vehicles than the adeno-associated and lentiviral vectors that are predominant today.

“We need to figure out how to re-dose AAV vectors if we want to provide functional cures for patients for the rest of their lives.”

How long a gene therapy’s benefit lasts is a critical question. In theory, it could last decades or potentially for life, depending on the treatment’s target.

But clinical evidence presented to date suggests that benefit for some therapies could wane over time. BioMarin, for example, presented data this year that it argued is proof its gene therapy could raise Factor VIII expression levels in patients with hemophilia A above the threshold for mild disease for at least eight years — a long time, to be sure, but not life-long.

Still, it’s an unusual objective. Much of gene therapy’s promise lies in the potential for it to be given just once and still deliver lasting benefits. And the therapies that have reached market — most notably Spark Therapeutics’ Luxturna, Novartis’ Zolgensma and Bluebird bio’s Zynteglo — are among the most expensive drugs to ever reach market. Were a gene therapy to be re-dosed, the current value proposition those drugmakers describe would need to be re-evaluated.

Curran recognizes that bringing down costs substantially will be essential to any attempt to advance a multi-use gene therapy. But Takeda might have an advantage. In buying Shire, the pharma inherited a viral vector manufacturing plant, originally built by Baxalta, that Curran calls the company’s “best kept secret.”

“It’s an enormous competitive advantage,” he said, adding that Takeda believes it’s among the industry’s top three facilities by production capacity. “Roche trying to acquire Spark, Novartis and AveXis — a significant component of value of those transactions was that these companies had actually invested in manufacturing capabilities.”

Curran emphasized that Takeda’s ambitions in gene therapy will require it to partner with academic leaders in the field, a playbook that it’s followed over the past three years as it’s worked to expand into cell therapy.

“In the cell space, there’s more innovation you can bring up into proof of principle milestones in academia,” said Andy Plump, Takeda’s head of R&D, in an interview.

“An academic can manipulate a cell, but it’s very hard in an academic setting to optimize a small molecule,” he added. “This is a space where Novartis, and now we, have been quite successful in creating those relationships.”

Takeda has put partnerships in place with Japan’s Center for iPS Cell Research and Application, GammaDelta, Noile-Immune Biotech, Memorial Sloan Kettering Cancer Center and, just this month, The University of Texas MD Anderson Cancer Center.

That last collaboration gives Takeda access to a chimeric antigen receptor-directed natural killer, or NK, cell therapy. The drugmaker believes NK cells could offer advantages over the T cells modified to create the currently available cell therapies Kymriah and Yescarta.

Most notably, MD Anderson’s approach uses NK cells isolated from umbilical cord blood, rather than extracting T cells from each individual patient — a time-consuming and expensive process that has complicated the market launch of Kymriah and Yescarta. Cord blood-derived NK cells are designed to be allogeneic, or administered “off the shelf.”